1. Field of Invention
The present invention relates to certain 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives that are prodrugs of compounds that modulate the activity of protein kinases (xe2x80x9cPKsxe2x80x9d). Pharmaceutical compositions comprising these compounds, methods of treating diseases related to abnormal PK activity utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.
2. State of the Art
The following is offered as background information only and is not admitted to be prior art to the present invention.
PKs are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell growth, differentiation and proliferation, i.e., virtually all aspects of cell life in one way or another depend on PK activity. Furthermore, abnormal PK activity has been related to a host of disorders, ranging from relatively non life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer) (see U.S. Pat. No. 5,792,783 which is incorporated herein by reference in its entirety).
In view of the apparent link between PK-related cellular activities and wide variety of human disorders, it is no surprise that a great deal of effort is being expended in an attempt to identify ways to modulate PK activity. Some of this effort has involved biomimetic approaches using large molecules patterned on those involved in the actual cellular processes (e.g., mutant ligands (U.S. Pat. No. 4,966,849); soluble receptors and antibodies (Published PCT Appl. WO 94/10202, Kendall and Thomas, Proc. Nat""l Acad. Sci., 90:10705-09 (1994), Kim, et al., Nature, 362:841-844 (1993)); RNA ligands (Jelinek, et al., Biochemistry, 33:10450-56); Takano, et al., Mol. Bio. Cell 4:358A (1993); Kinsella, et al., Exp. Cell Res. 199:56-62 (1992); Wright, et al., J. Cellular Phys., 152:448-57) and tyrosine kinase inhibitors (Published PCT Appls. WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; U.S. Pat. No. 5,330,992; Mariani, et al., Proc. Am. Assoc. Cancer Res., 35:2268 (1994)).
In addition to the above, attempts have been made to identify small molecules which act as PK inhibitors. For example, bis-monocylic, bicyclic and heterocyclic aryl compounds (Published PCT Appl. WO 92/20642), vinyleneazaindole derivatives (Published PCT Appl. WO 94/14808) and 1-cyclopropyl-4-pyridylquinolones (U.S. Pat. No. 5,330,992) have been described as tyrosine kinase inhibitors. Styryl compounds (U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606), quinazoline derivatives (EP App. No.0 566 266 A1), selenaindoles and selenides (Published PCT Appl. WO 94/03427), tricyclic polyhydroxylic compounds (Published PCT Appl. WO 92/21660), benzylphosphonic acid compounds (Published PCT Appl. WO 91/15495) and indolinone compounds (U.S. Pat. No. 5,792,783) have all been described as PTK inhibitors useful in the treatment of cancer. However these compounds have limited utility because of toxicity or poor bioavailability. Accordingly, there is a need for compounds that overcome these limitations. The compounds of the present invention fulfil this need.
The present invention is directed to certain 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives that are prodrugs of compounds that exhibit PK modulating ability and are therefore useful in treating disorders related to abnormal PK activity.
Accordingly, in one aspect, the present invention relates a compound of Formula (I): 
wherein:
R1 and R2 are independently selected from the group consisting of hydrogen, halo, alkyl, alkylthio, nitro, trihalomethyl, hydroxy, hydroxyalkyl, alkoxy, cyano, aryl, heteroaryl, xe2x80x94C(O)R7 (where R7 is selected from the group consisting of alkyl, amino, hydroxy, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, heterocycle, and aminoalkylamino), xe2x80x94NR8R9, xe2x80x94NR8C(O)R9, xe2x80x94SO2R8, and xe2x80x94S(O)2NR8R9 (where R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl, or R8 and R9 together with the nitrogen to which they are attached form a saturated heterocycloamino);
R3 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, xe2x80x94C(O)R7 (where R7 is as defined above), aryl, and heteroaryl;
R4 is selected from the group consisting of hydrogen, alkyl, xe2x80x94C(O)R7 (where R7 is as defined above), aryl, and heteroaryl;
R5 is selected from the group consisting of hydrogen and xe2x80x94COR10 where R10 is alkyl, alkoxy, hydroxy, aryl, aryloxy, heteroaryl, heterocyle, alkylamino, dialkylamino, or xe2x80x94NR11R12 where R11 is hydrogen or alkyl, and R12 is aminoalkyl, hydroxyalkyl, acetylalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, or heterocyclylalkyl; wherein the alkyl chain in aminoalkyl, heteroaralkyl, heteroaralkyl, or heterocyclylalkyl is optionally substituted with one or two hydroxy group(s); or R4 and R5 together form xe2x80x94(CH2)4xe2x80x94 or xe2x80x94(CH2)mCO(CH2)nxe2x80x94 wherein n is 0 to 3, n is 0 to 3 provided that n+m is 3;
R6 is:
(a) xe2x80x94OR13 wherein R13 is alkyl, trifluoromethyl, carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, alkoxyalkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, monosaccharides and heterocyclylalkyl; wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, heteroaralkyl, heterocyclylalkyl, hydroxyalkyl, or alkoxyalkyl is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen, xe2x80x94NR14xe2x80x94 (where R14 is hydrogen or alkyl), xe2x80x94Sxe2x80x94, or xe2x80x94SO2xe2x80x94; or
(b) xe2x80x94NR15R16 where are R15 and R16 are independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclylalkyl wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, heteroaralkyl, heterocyclylalkyl, hydroxyalkyl, or alkoxyalkyl is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in the alkyl chain are optionally replaced by oxygen, xe2x80x94NR17xe2x80x94 (where R17 is hydrogen or alkyl), xe2x80x94Sxe2x80x94, or xe2x80x94SO2xe2x80x94; or
R15 and R16 together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino; or a pharmaceutically acceptable salt thereof.
Specifically, the compounds of the present invention convert in vivo to compounds of Formula (II): 
that exhibit PK modulating ability, in particular PK inhibiting ability, and are therefore useful in treating disorders related to abnormal PK activity. The active compounds (II) formed from the compounds of the present invention are described in U.S. Pat. No. 5,792,783, and U.S. patent application Ser. No. 09/783,264, filed on Feb. 15, 2001, and titled xe2x80x9cPYRROLE SUBSTITUTED 2-INDOLINONE PROTEIN KINASE INHIBITORSxe2x80x9d which are hereby incorporated by reference.
The compounds of the present invention have advantages over compounds of Formula (II) by virtue of improved solubility and formulability. For example, it has been discovered that prodrugs of compound (II) where R1, R2, and R5 are hydrogen and R3 and R4 are methyl provide improved aqueous solubility over the parent compound. It is contemplated that similar enhanced bioavailability will be observed with other compounds within the scope of the present invention.
A general description of the advantages and uses of prodrugs as pharmaceutically useful compounds is given in an article by Waller and George in Br. J. Clin. Pharmac., Vol. 28, pp. 497-507, 1989.
By way of illustration, the following compounds of the present invention are converted to the indicated PK inhibitors of Formula (II).
In a second aspect this invention is directed to a pharmaceutical composition comprising one or more compound(s) of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In a third aspect, this invention is directed to a method of treating diseases mediated by abnormal protein kinase activity, in particular, receptor tyrosine kinases (RTKs), non-receptor protein tyrosine kinases (CTKs) and serine/threonine protein kinases (STKs), in an organism, in particular humans, which method comprises administering to said organism a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable excipient. Such diseases include by way of example and not limitation, cancer, diabetes, hepatic cirrhosis, cardiovascular disease such as atherosclerosis, angiogenesis, immunological disease such as autoimmune disease and renal disease. Specifically, the diseases mediated by EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFRxcex1, PDGFRxcex2, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R, FGFR-4R, Src, Frk, Btk, Csk, Abl, ZAP70, Fes/Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, Yrk, CDK2 and Raf.
In a fourth aspect, this invention is directed to a method of modulating the catalytic activity (e.g., inhibiting the catalytic activity) of PKs, in particular receptor tyrosine kinases (RTKs), non-receptor protein tyrosine kinases (CTKs) and serine/threonine protein kinases (STKs), using a compound of this invention or a pharmaceutical composition comprising a compound of this invention and a pharmaceutically acceptable excipient. The method may be carried out in vitro or in vivo. In particular, the receptor protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of EGF, HER2, HER3, HER4, IR, IGF-LR, IRR, PDGFRxcex1, PDGFRxcex2, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R. The cellular tyrosine kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes/Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The serine-threonine protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of CDK2 and Raf.
In a fifth aspect, this invention is directed to the use of a compound of Formula (I) in the preparation of a medicament which is useful in the treatment of a disease mediated by abnormal PK activity.
In a sixth aspect, this invention is directed to intermediates of Formula (III) useful for preparing the compounds of Formula (I): 
where R1-R5 are as defined in compounds of Formula (I) above and LG is a leaving group, under acylating reaction conditions. Preferably LG is imidazol-1-yl or halo such as chloro, bromo or iodo.
In a seventh aspect, this invention is directed to a method of preparing a compound of Formula (I) which method comprises reacting a compound of Formula (III): 
where LG is a leaving group, under acylating reaction conditions:
(i) with an alcohol of formula R13OH where R13 is defined in Formula (I), optionally in the presence of an acid or base to provide a compound of Formula (I); or
(ii) with an amine of formula xe2x80x94NR15R16 where R15 and R16 are as defined in Formula (I) to provide a compound of Formula (I);
(iii) optionally preparing an acid addition salt; and
(iv) optionally modifying any of the R1-R5 groups.
Preferably, LG is chloro or imidazol-1-yl.
Lastly, this invention is directed to a method of identifying a chemical compound that modulates the catalytic activity of a protein kinase which method comprises by contacting cells expressing said protein kinase with said compound and then monitoring said cells for an effect.
Unless otherwise stated the following terms used in the specification and claims have the meanings discussed below:
xe2x80x9cAlkylxe2x80x9d refers to a saturated straight or branched hydrocarbon radical of 1 to 20 carbon atoms. More preferably, it is a medium size alkyl radical having 1 to 10 carbon atoms e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like. Most preferably, it is lower alkyl having 1 to 4 carbon atoms e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, or tert-butyl, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means a saturated straight or branched monovalent hydrocarbon radical of one to six carbon atoms substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.
xe2x80x9cAlkoxyalkylxe2x80x9d means a saturated straight or branched monovalent hydrocarbon radical of one to six carbon atoms substituted with one or two alkoxy groups as defined above, e.g., methoxymethyl, 2-methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, and the like.
xe2x80x9cAminoalkylxe2x80x9d means a saturated straight or branched monovalent hydrocarbon radical of one to six carbon atoms substituted with one or two xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 are independently selected from hydrogen, alkyl, or acyl, e.g., 2-aminoethyl, 2-N-ethylaminoethyl, 2-N,N-diethylaminoethyl, 2-N,N-diethylaminopropyl, 2-N-acetylaminoethyl, and the like.
xe2x80x9cAminoalkylaminoxe2x80x9d means an xe2x80x94NHR group wherein R is an aminoalkyl group as defined above, e.g., 2-aminoethylamino, 2-N-ethylaminoethylamino, 2-N,N-diethylaminoethylamino, 2-N,N-diethylaminopropylamino, 2-N-acetylaminoethylamino, and the like.
xe2x80x9cAcylxe2x80x9d means a radical xe2x80x94C(O)R where R is hydrogen, lower alkyl, or haloalkyl as defined herein, e.g., formyl, acetyl, trifluoroacetyl, butanoyl, and the like.
xe2x80x9cCarboxyalkylxe2x80x9d means a saturated straight or branched monovalent hydrocarbon radical of one to six carbon atoms substituted with one or two xe2x80x94COOH group e.g., carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and the like.
xe2x80x9cPhosphonooxyalkylxe2x80x9d means a saturated straight or branched monovalent hydrocarbon radical of one to six carbon atoms substituted with a xe2x80x94OPO3H group, or xe2x80x94OPO(OMe2) group e.g., phosphonooxymethyl, 2-phosphonooxyethyl, 3-phosphonooxy-propyl, and the like.
xe2x80x9cSulfooxyalkylxe2x80x9d means a saturated straight or branched monovalent hydrocarbon radical of one to six carbon atoms substituted with a xe2x80x94OSO3H group, or xe2x80x94OSO(OMe2) group e.g., sulfooxymethyl, 2-sulfoxyethyl, 2-dimethoxysulfoxyethyl, 3-sulfooxypropyl, and the like.
xe2x80x9cAlkylthioxe2x80x9d means a radical xe2x80x94SR where R is alkyl as defined above, e.g., methylthio, ethylthio, butylthio, and the like.
xe2x80x9cAlkenylxe2x80x9d refers to a lower alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
xe2x80x9cSubstituted alkenylxe2x80x9d refers to an alkenyl group as defined above which is substituted with one, two or three groups selected from halo, carboxy, xe2x80x94C(O)OR where R is alkyl, amino, or nitro.
xe2x80x9cArylxe2x80x9d refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, the aryl group is substituted with one or more, more preferably one, two or three, even more preferably one or two substituents independently selected from the group consisting of lower alkyl, alkenyl, substituted alkenyl, trihaloalkyl, halo, hydroxy, alkoxy, mercapto, alkylthio, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R18S(O)xe2x80x94, R18S(O)2xe2x80x94,
xe2x80x94C(O)OR18, R18C(O)Oxe2x80x94, and xe2x80x94NR18R19, with R18 and R19 are independently selected from hydrogen, lower alkyl, aryl substituted with halo, hydroxy, alkoxy, amino, carboxy, nitro or cyano, heteroaryl substituted with halo, hydroxy, alkoxy, amino, carboxy, nitro or cyano, aralkyl wherein the aryl ring is substituted with halo, hydroxy, alkoxy, amino, carboxy, nitro or cyano, or heteroaralkyl wherein the heteroaryl ring is substituted with halo, hydroxy, alkoxy, amino, carboxy, nitro or cyano. Preferably, the aryl group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, hydroxy, cyano, N-amido, mono- or dialkylamino, carboxy, or N-sulfonamido.
xe2x80x9cHeteroarylxe2x80x9d refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, triazole, tetrazole, triazine, and carbazole. The heteroaryl group may be substituted or unsubstituted. When substituted, the the heteroaryl ring is substituted with one or more, more preferably one, two, or three, even more preferably one or two substituents, independently selected from the group consisting of lower alkyl, trihaloalkyl, halo, nitro, amino, hydroxy, alkoxy, mercapto, alkylthio, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R18S(O)xe2x80x94, R18O)2xe2x80x94, xe2x80x94C(O)OR18, R18C(O)Oxe2x80x94, and xe2x80x94NR18R19, with R18 and R19 as defined above. Preferably, the heteroaryl group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, hydroxy, mercapto, cyano, N-amido, mono or dialkylamino, carboxy, or N-sulfonamido.
xe2x80x9cHeterocyclexe2x80x9d means a saturated cyclic radical of 3 to 8 ring atoms in which one, two or three ring atoms are heteroatoms selected from N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocyclyl ring may be optionally substituted independently with one or more, preferably one, two, or three substituents selected from lower alkyl (wherein the lower alkyl may be optionally substituted with one or two substituents independently selected from carboxy or ester group), haloalkyl, cyanoalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl, heteroaralkyl, and xe2x80x94COR (where R is alkyl). More specifically the term heterocyclyl includes, but is not limited to, tetrahydropyranyl, 2,2-dimethyl-1,3-dioxolane, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 4-ethyloxycarbonylpiperazino, 3-oxopiperazino, 2-imidazolidone, 2-pyrrolidinone, 2-oxohomopiperazino, tetrahydropyrimidin-2-one, and the derivatives thereof. Preferably, the heterocycle group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, lower alkyl substituted with carboxy, ester, hydroxy, or mono or dialkylamino.
xe2x80x9cSaturated heterocycloaminoxe2x80x9d means a saturated cyclic radical of 3 to 8 ring atoms in which at least one of the ring atoms is nitrogen and optionally where one or two additionally ring atoms are heteroatoms selected from NRa (where Ra is alkyl, substituted alkyl acyl, aryl, or heteroaryl), O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocycloamino ring may be optionally substituted independently with one, two, or three substituents selected from alkyl (optionally substituted with one or two substituents independently selected from carboxy or ester group), haloalkyl, cyanoalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl, heteroaralkyl, and xe2x80x94COR (where R is alkyl). More specifically the term heterocycloamino includes, but is not limited to, piperidyn-1-yl, piperazin-1-yl, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2,5-dioxo-pyrrolidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 4-ethyloxycarbonylpiperazin-1-yl, 3-oxopiperazin-1-yl, 2-imidazolidon-1-yl, 2-pyrrolidinon-1-yl, 2-oxohomopiperazino, tetrahydropyrimidin-2-one, and the derivatives thereof. The heterocycloamino group is a subset of the heterocycle group defined above.
xe2x80x9cUnsaturated heterocycloaminoxe2x80x9d means a non-aromatic cyclic radical of 4 to 8 ring atoms containing one or two double bonds within the ring provided that the ring is not aromatic, and in which at least one of the ring atoms is nitrogen and optionally where one or two additionally ring atoms are heteroatoms independently selected from NRa (where Ra is alkyl, substituted alkyl acyl, aryl, or heteroaryl), O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C where one or two C atoms may optionally be replaced by a carbonyl group. The heterocycloamino ring may be optionally substituted independently with one, two, or three substituents selected from alkyl (wherein the alkyl group can be optionally substituted one or two substituents independently selected from carboxy or ester group), haloalkyl, cyanoalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl, heteroaralkyl, and xe2x80x94COR (where R is alkyl).
xe2x80x9cHydroxyxe2x80x9d refers to an xe2x80x94OH group.
xe2x80x9cAlkoxyxe2x80x9d refers to an xe2x80x94OR group where R is lower alkyl as defined above. Representative examples include, but are not limited to, e.g., methoxy, ethoxy, propoxy, butoxy, and the like.
xe2x80x9cAryloxyxe2x80x9d refers to both an xe2x80x94OR where R is an aryl group, as defined herein. Representative examples include, but are not limited to, phenoxy, anthryloxy and the like, and derivatives thereof.
xe2x80x9cHeteroaryloxyxe2x80x9d refers to both an xe2x80x94OR where R is a heteroaryl group, as defined herein. Representative examples include, but are not limited to, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
xe2x80x9cAcetylalkylxe2x80x9d means a lower alkyl group as defined above carrying a xe2x80x94C(O)CH3 group, e.g., acetylmethyl, acetylethyl, acetylpropyl, and the like.
xe2x80x9cCyanoalkylxe2x80x9d means a lower alkyl group as defined above carrying a xe2x80x94CN group e.g., cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 2-cyanopropyl, and the like.
xe2x80x9cAlkoxycarbonylalkylxe2x80x9d means a lower alkyl group as defined above carrying a xe2x80x94COOR group where R is lower alkyl e.g., methoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonyl or ethoxycarbonylpropyl, 2-methoxycarbonyl or ethoxycarbonylpropyl, and the like.
xe2x80x9cHaloxe2x80x9d group refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
xe2x80x9cTrihalomethylxe2x80x9d group refers to a xe2x80x94CX3 group wherein X is a halo group as defined herein.
xe2x80x9cCyanoxe2x80x9d refers to a xe2x80x94Cxe2x95x90N group.
xe2x80x9cS-sulfonamidoxe2x80x9d refers to a xe2x80x94S(O)2NR18R19 group, with R18 and R19 as defined herein.
xe2x80x9cN-sulfonamidoxe2x80x9d refers to a xe2x80x94NR18S(O)2R19 group, with R18 and R19 as defined herein.
xe2x80x9cO-carbamylxe2x80x9d group refers to a xe2x80x94OC(O)NR18R19 group with R18 and R19 as defined herein.
xe2x80x9cN-carbamylxe2x80x9d refers to an R18OC(O)NR19xe2x80x94 group, with R18 and R19 as defined herein.
xe2x80x9cO-thiocarbamylxe2x80x9d refers to a xe2x80x94OC(S)NR18R19 group with R18 and R19 as defined herein.
xe2x80x9cN-thiocarbamylxe2x80x9d refers to a R18OC(S)NR19xe2x80x94 group, with R18 and R19 as defined herein.
xe2x80x9cAminoxe2x80x9d refers to an xe2x80x94NR18R19 group, wherein R18 and R19 are both hydrogen.
xe2x80x9cC-amidoxe2x80x9d refers to a xe2x80x94C(O)NR18R19 group with R18 and R19 as defined herein.
xe2x80x9cN-amidoxe2x80x9d refers to a R18C(O)NR19xe2x80x94 group, with R18 and R19 as defined herein.
xe2x80x9cNitroxe2x80x9d refers to a xe2x80x94NO2 group.
xe2x80x9cHaloalkylxe2x80x9d means an alkyl as defined above that is substituted with one or more same or different halo atoms, e.g., xe2x80x94CH2Cl, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CCl3, and the like.
xe2x80x9cAralkylxe2x80x9d means alkyl as defined above which is substituted with an aryl group as defined above, e.g., xe2x80x94CH2phenyl, xe2x80x94(CH2)2phenyl, xe2x80x94(CH2)3phenyl, CH2CH(CH3)CH2phenyl, and the like and derivatives thereof.
xe2x80x9cHeteroaralkylxe2x80x9d group means alkyl as defined above which is substituted with a heteroaryl group, e.g., xe2x80x94CH2pyridinyl, xe2x80x94(CH2)2pyrimidinyl, xe2x80x94(CH2)3imidazolyl, and the like, and derivatives thereof.
xe2x80x9cHeterocyclylalkylxe2x80x9d group means alkyl as defined above which is substituted with a heterocycle group, e.g., xe2x80x94CH2pyrrolidin-1-yl, xe2x80x94(CH2)2piperidin-1-yl, and the like, and derivatives thereof.
xe2x80x9cAlkylaminoxe2x80x9d means a radical xe2x80x94NHR where R is alkyl, e.g., methylamino, (1-methylethyl)amino, and the like.
xe2x80x9cDialkylaminoxe2x80x9d means a radical xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 are independently alkyl e.g., dimethylamino, methylethylamino, di(1-methylethyl)amino, and the like.
xe2x80x9cMonosaccharidesxe2x80x9d means sugars that are not hydrolyzable into smaller units e.g., glucose, galactose, and the like.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may, but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9cheterocycle group optionally substituted with an alkyl groupxe2x80x9d means that the alkyl may but need not be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
The terms xe2x80x9c2-indolinonexe2x80x9d, xe2x80x9cindolin-2-onexe2x80x9d and xe2x80x9c2-oxindolexe2x80x9d are used interchangeably herein to refer to a molecule having the chemical structure: 
The term xe2x80x9cpyrrolexe2x80x9d refers to a molecule having the 
chemical structure:
Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed xe2x80x9cisomersxe2x80x9d. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and those that are non-supetimposable mirror images of each other are termed xe2x80x9cenantiomersxe2x80x9d. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the Rxe2x80x94 and Sxe2x80x94 sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (xe2x88x92)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a xe2x80x9cracemic mixturexe2x80x9d.
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)xe2x80x94 or (S)xe2x80x94 stereoisomers or as mixtures thereof. For example, if the R6 substituent in a compound of formula (I) is 2-hydroxyethyl, then the carbon to which the hydroxy group is attached is an asymmetric center and therefore the compound of Formula (I) can exist as an (R)xe2x80x94 or (S)-stereoisomer. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition J. March, John Wiley and Sons, New York, 1992).
The compounds of Formula (I) may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds described herein may adopt an E or a Z configuration about the double bond connecting the 2-indolinone moiety to the pyrrole moiety or they may be a mixture of E and Z. This invention encompasses any tautomeric or structural isomeric form and mixtures thereof which possess the ability to modulate RTK, CTK and/or STK activity and is not limited to any one tautomeric or structural isomeric form.
A xe2x80x9cpharmaceutical compositionxe2x80x9d refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
It is contemplated that a compound of Formula (I) would be metabolized by enzymes in the body of the organism such as human being to generate a metabolite that can modulate the activity of the protein kinases. Such metabolites are within the scope of the present invention.
As used herein, a xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
An xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) acid addition salt which is obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perhcloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like, preferably hydrochloric acid or (L)-malic acid; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
xe2x80x9cPKxe2x80x9d refers to receptor protein tyrosine kinase (RTKs), non-receptor or xe2x80x9ccellularxe2x80x9d tyrosine kinase (CTKs) and serine-threonine kinases (STKs).
xe2x80x9cMethodxe2x80x9d refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by, practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts.
xe2x80x9cModulationxe2x80x9d or xe2x80x9cmodulatingxe2x80x9d refers to the alteration of the catalytic activity of RTKs, CTKs and STKs. In particular, modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTK, CTK or STK is exposed or, more preferably, the inhibition of the catalytic activity of RTKs, CTKs and STKs.
xe2x80x9cCatalytic activityxe2x80x9d refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylation of serine and threonine under the influence, direct or indirect, of STKs.
xe2x80x9cContactingxe2x80x9d refers to bringing a compound of this invention and a target PK together in such a manner that the compound can affect the catalytic activity of the PK, either directly, i.e., by interacting with the kinase itself, or indirectly, i.e., by interacting with another molecule on which the catalytic activity of the kinase is dependent. Such xe2x80x9ccontactingxe2x80x9d can be accomplished in vitro, i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a PK of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment. In this context, the ability of a particular compound to affect a PK related disorder, i.e., the IC50 of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, multiple methods exist, and are well-known to those skilled in the art, to get the PKs in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques.
xe2x80x9cIn vitroxe2x80x9d refers to procedures performed in an artificial environment such as, e.g., without limitation, in a test tube or culture medium.
xe2x80x9cIn vivoxe2x80x9d refers to procedures performed within a living organism such as, without limitation, a mouse, rat or rabbit.
xe2x80x9cPK related disorder,xe2x80x9d xe2x80x9cPK driven disorder,xe2x80x9d and xe2x80x9cabnormal PK activityxe2x80x9d all refer to a condition characterized by inappropriate, i.e., decreased or, more commonly, increased, PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs, (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth, or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth. Increased activity of a PK refers to either amplification of the gene encoding a particular PK or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more of the symptoms of the cellular disorder increases). Decreased activity is, of course, the converse, wherein the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases.
xe2x80x9cTreatxe2x80x9d, xe2x80x9ctreatingxe2x80x9d and xe2x80x9ctreatmentxe2x80x9d refer to a method of alleviating or abrogating a PK mediated cellular disorder and/or its attendant symptoms. With regard particularly to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease will be reduced.
xe2x80x9cOrganismxe2x80x9d refers to any living entity comprised of at least one cell. A living organism can be as simple as, for example, a single eukaryotic cell or as complex as a mammal, including a human being.
xe2x80x9cTherapeutically effective amountxe2x80x9d refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of:
(1) reducing the size of a tumor;
(2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis;
(3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and/or,
(4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer.
xe2x80x9cMonitoringxe2x80x9d means observing or detecting the effect of contacting a compound with a cell expressing a particular PK. The observed or detected effect can be a change in cell phenotype, in the catalytic activity of a PK or a change in the interaction of a PK with a natural binding partner. Techniques for observing or detecting such effects are well-known in the art.
The above-referenced effect is selected from a change or an absence of change in a cell phenotype, a change or absence of change in the catalytic activity of said protein kinase or a change or absence of change in the interaction of said protein kinase with a natural binding partner in a final aspect of this invention.
xe2x80x9cCell phenotypexe2x80x9d refers to the outward appearance of a cell or tissue or the biological function of the cell or tissue. Examples, without limitation, of a cell phenotype are cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis, and nutrient uptake and use. Such phenotypic characteristics are measurable by techniques well-known in the art.
xe2x80x9cNatural binding partnerxe2x80x9d refers to a polypeptide that binds to a particular PK in a cell. Natural binding partners can play a role in propagating a signal in a PK-mediated signal transduction process. A change in the interaction of the natural binding partner with the PK can manifest itself as an increased or decreased concentration of the PK/natural binding partner complex and, as a result, in an observable change in the ability of the PK to mediate signal transduction.
xe2x80x9cPro-drugsxe2x80x9d means a compound which releases an active parent drug in vivo when administered to a mammalian subject.
While the broadest definition is set forth in the Summary of the Invention, certain compounds of Formula (I) set forth below are preferred.
(1) A preferred group of compounds of Formula (I) is that wherein R1 and R2 are hydrogen or R1 is hydrogen and R2 is halo, preferably R2 is chloro or fluoro, most preferably fluoro and is located at the 5-position of the indolinone ring.
(2) Another preferred group of compounds is that wherein R1 is hydrogen and R2 is alkoxy, cyano, aryl, xe2x80x94SO2R8 where R8 is lower alkyl, aryl or heteroaryl, or xe2x80x94S(O)2NR8R9 wherein R8 is hydrogen and R9 is hydrogen, aryl, heteroaryl, or lower alkyl, preferably R2 is hydrogen, methoxy, ethoxy, phenyl, phenylsulfonyl, 3-chlorophenylaminosulfonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, phenylaminosulfonyl, pyridin-3-yl-aminosulfonyl, or isopropylaminosulfonyl and is located at the 5-position of the indolinone ring.
(3) A third preferred group of compounds is that wherein:
R3 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, hydroxyalkyl, aryl, heteroaryl, and xe2x80x94C(O)R7 (wherein R7 is hydroxy, amino, lower alkyl, aminoalkylamino or aryl), more preferably hydrogen, methyl, ethyl, isopropyl, n-, iso- or tert-butyl, phenyl, even more preferably methyl or phenyl, most preferably methyl; and
R4 is selected from the group consisting of hydrogen and alkyl, preferably hydrogen, methyl, ethyl, iso-propyl, tert-butyl, iso-butyl, or n-butyl, more preferably methyl.
(4) A fourth more preferred group of compounds is that wherein
R5 is:
(i) hydrogen; or
(ii) xe2x80x94COR10 where R10 is xe2x80x94NR11R12 where R11 is hydrogen or lower alkyl and R12 is aminoalkyl wherein the alkyl chain is optionally substituted with hydroxy, more preferably R5 is 3-amino-2-hydroxypropylaminocarbonyl, N-(2-dimethylaminoethyl)-aminocarbonyl, N-(2-diethylaminoethyl)-N-methylaminocarbonyl, N-(3-dimethylaminopropyl)aminocarbonyl, N-(2-diethylaminoethyl)-aminocarbonyl, N-(3-ethylaminopropyl)aminocarbonyl, N-(3-ethylamino-2-hydroxypropyl)aminocarbonyl, N-(3-diethylamino-propyl)aminocarbonyl, 3-amino-2-hydroxypropylaminocarbonyl, 3-dimethylamino-2-hydroxypropylaminocarbonyl, 3-diethylamino-2-hydroxypropylaminocarbonyl, or N-(3-diethylamino-2-hydroxy-propyl)aminocarbonyl, more preferably, N-(2-diethylaminoethyl)-aminocarbonyl or N-(ethylaminoethyl)aminocarbonyl; or
(iii) xe2x80x94COR10 where R10 is xe2x80x94NR11R12 where R11 is hydrogen or lower alkyl and R12 is heterocyclylalkyl wherein the alkyl group is optionally substituted with hydroxy, preferably R5 is 3-pyrrolidin-1-yl-propylaminocarbonyl, 3-morpholin-4-ylpropyl-aminocarbonyl, 2-pyrrolidin-1-ylethylaminocarbonyl, 2-morpholin-4-ylethylaminocarbonyl, 2-(4-methylpiperazin-1-yl)ethyl-aminocarbonyl, 2-(3,5-dimethylpiperazin-1-yl)ethylaminocarbonyl, 2-(3-ethoxycarbonylpiperazin-1-yl)ethylaminocarbonyl, 2-(3-oxopiperazin-1-yl)ethylaminocarbonyl, 2-(imidazolidin-1-yl-2-one)ethylaminocarbonyl, 2-(tetrahydropyrimidin-1-yl-2-one)-ethylaminocarbonyl, 2-(2-oxopyrrolidin-1-yl)ethylamino-carbonyl, 3-(4-methyl-piperazin-1-yl)propylaminocarbonyl, 3-(3-ethoxy-carbonylpiperazin-1-yl)propylaminocarbonyl, 3-(3-oxopiperazin-1-yl)propylaminocarbonyl, 3-(imidazolidin-1-yl-2-one)propyl-aminocarbonyl, 3-(tetrahydro-pyrimidin-1-yl-2-one)-propylaminocarbonyl, 3-(2-oxopyrrolidin-1-yl)propylamino-carbonyl, 2-(2-oxohomopiperidin-1-yl)ethylamino-carbonyl, 3-(2-oxohomopiperidin-1-yl)propylaminocarbonyl, 3-morpholin-2-hydroxypropylaminocarbonyl, 3-pyrrolidin-1-yl-2-hydroxypropyl-aminocarbonyl, or 3-(4-methylpiperazin-1-yl)-2-hydroxypropylaminocarbonyl, even more preferably 2-pyrrolidin-1-ylethylaminocarbonyl; or
(iv) xe2x80x94COR10 where R10 is xe2x80x94NR11R12 where R11 is hydrogen or alkyl and R12 is hydroxyalkyl or heteroaralkyl wherein the alkyl group in heteroaralkyl is optionally substituted with one or two hydroxy groups, preferably R5 is 3-hydroxypropylamino-carbonyl, 2-hydroxyethylaminocarbonyl, triazin-1-ylpropyl-aminocarbonyl, triazin-1-ylethyl-aminocarbonyl, 3-imidazol-1-ylpropyl-aminocarbonyl, pyridin-4-ylmethylamino-carbonyl, 3-[1,2,3]-triazol-1-yl-2-hydroxypropyl-aminocarbonyl, 3-[1,2,3]-triazol-2-yl-2-hydroxypropyl-aminocarbonyl, or 2-pyridin-2-ylethylamino-carbonyl;
xe2x80x94COR10 where R10 is heterocycle, preferably a heterocycle of 4 or 6 ring atoms containing one or two nitrogen and optionally an oxygen, more preferably R5 is pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, or piperazin-1-ylcarbonyl.
(5) A fifth preferred group of compounds is that wherein R6 is xe2x80x94OR13 wherein R13 is lower alkyl, trifluoromethyl, carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, alkoxyalkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, monosaccharides or heterocyclylalkyl wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, heterocyclylalkyl, heteroaralkyl, or alkoxyalkyl is optionally substituted with one or two hydroxy group(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen, or xe2x80x94NR14xe2x80x94(where R14 is hydrogen or alkyl), preferably R13 is alkyl, aminoalkyl, carboxyalkyl, phosphonooxyalkyl, sulfooxyalkyl, monosaccharides, hydroxyalkyl, alkoxyalkyl and heterocyclylalkyl (wherein the alkyl chain is optionally substituted with one or two hydroxy group(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen), more preferably methyl, 2-methoxyethyl, 2-(2-methoxyethoxy)ethyl, 2-(2-hydroxyethoxy)-ethyl, 2-hydroxyethyl, 3,4,5,6-tetrahydroxy-tetrahydropyran-2-ylmethyl, xe2x80x94(CH2)2OP(O) (OCH3)2, xe2x80x94(CH2) (CHOH) (CH2)OP(O) (OH)2, xe2x80x94(CH2)2OP(O) (OH)2, 2,3-dihydroxypropyl, 2-(diethoxyphosphonooxy)-ethyl, 3-(dimethoxy-phosphonooxy)propyl, 3-(diethoxyphosphono-oxy)-propyl, 3-phosphonooxypropyl, 2-hydroxy-3-(dimethoxy-phosphonooxy)-propyl, 2-hydroxy-3-(diethoxyphosphonooxy)propyl, xe2x80x94(CH2)2OSO3H, xe2x80x94(CH2)2OSO3Na+, xe2x80x94(CH2)3OSO3H, xe2x80x94(CH2)3OSO3Na+, 2-diethylaminoethyl, carboxymethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, 2-(2,5-dioxopyrrolidin-1-yl)ethyl, 2-carboxy-2-hydroxyethyl, 3-hydroxypropyl, 2-morpholin-4-ylethyl, pyrrolidin-1-ylethyl, pyrolin-1-yl, 2-hydroxy-3-morpholin-4-ylpropyl, 4-(2-carboxyvinylidene)phenyl, 4-carboxyphenyl, or 2-hydroxy-3-pyrrolidin-1-ylpropyl. Even more preferably R13 is 2-dimethoxyphosphonooxy)ethyl, 2-(diethoxyphosphonooxy)ethyl, 2-phosphonooxyethyl, 3-(dimethoxyphosphonooxy)propyl, 3-(diethoxyphosphonooxy)propyl, 3-phosphonooxypropyl, 3-sulfooxypropyl, 2-hydroxy-3-(dimethoxyphosphonooxy)propyl, 2-hydroxy-3-(diethoxy-phosphonooxy)propyl, 2-hydroxy-3-phosphonooxypropyl, xe2x80x94(CH2)2OSO3Na+, xe2x80x94(CH2)3OSO3Na+, 2,3-dihydroxypropyl, 2-hydroxyethyl or 3-hydroxypropyl.
(6) A sixth more preferred group of compounds is that wherein R6 is xe2x80x94NR15R16 where R15 and R16 are independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclylalkyl; wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, heterocyclylalkyl, heteroaralkyl, hydroxyalkyl, or alkoxyalkyl is optionally substituted with one or two hydroxy group(s) and further wherein one or two carbon atoms in the alkyl chain are optionally replaced by oxygen, xe2x80x94NR17xe2x80x94 (where R17 is hydrogen or alkyl), xe2x80x94Sxe2x80x94, or xe2x80x94SO2xe2x80x94; or R15 and R16 together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino. More preferably, R15 is hydrogen, and R6 is alkyl, aminoalkyl, carboxyalkyl, phosphonooxyalkyl, sulfooxyalkyl, monosaccharides, hydroxyalkyl, alkoxyalkyl and heterocyclylalkyl (wherein the alkyl chain is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen), even more preferably 2-hydroxy-3-morpholin-4-ylpropyl, pyrolin-1-yl, 5-fluoro-2,4-dioxo-pyrimidin-1-yl, 2-hydroxy-3-pyrrolidin-1-yl-propyl, 2-carboxypyrrolidin-1-yl, 2-hydroxy-3-dimethylamino-propyl, 2-hydroxy-3-diethylaminopropyl, 2-hydroxy-3-(4-methylpiperazin-1-yl)propyl, 3-[1,2,3]-triazol-1-yl-2-hydroxypropyl, or 2-hydroxy-3-[1,2,3]-triazol-2-ylpropyl.
(7) Yet another preferred group of compound of represent by Formula (Ia): 
wherein:
R3 is selected from the group consisting of hydrogen, alkyl, xe2x80x94C(O)R7 (where R7 is selected from the group consisting of lower alkyl, amino, hydroxy, alkoxy, aryl, heteroaryl, aryloxy, and heteroaryloxy), or aryl;
R4 is selected from the group consisting of hydrogen, alkyl, or xe2x80x94C(O)R7 (where R7 is as defined above);
R6 is:
(i) xe2x80x94OR13 wherein R13 is alkyl, trifluoromethyl, carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, alkoxyalkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, monosaccharides and heterocyclylalkyl wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, heterocyclylalkyl, hydroxyalkyl or alkoxyalkyl is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen, xe2x80x94NR14xe2x80x94 (where R14 is hydrogen or alkyl), xe2x80x94Sxe2x80x94, or xe2x80x94SO2xe2x80x94; or
(ii) xe2x80x94NR15R 16 where are R15 and R16 are independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclylalkyl; wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, heterocyclylalkyl, or alkoxyalkyl is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in the alkyl chain are optionally replaced by oxygen, xe2x80x94NR17xe2x80x94 (where R17 is hydrogen or alkyl), xe2x80x94Sxe2x80x94, or xe2x80x94SO2xe2x80x94; or
R15 and R16 together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino; or
a pharmaceutically acceptable salt thereof.
Preferably, R3 and R4 are alkyl, more preferably methyl.
Within this group, a more preferred group of compounds is that wherein R6 is xe2x80x94OR13 wherein R13 is lower alkyl, trifluoromethyl, carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, alkoxyalkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, monosaccharides or heterocyclylalkyl; wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, heterocyclylalkyl, hydroxyalkyl, heteroaralkyl, or alkoxyalkyl is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen, or xe2x80x94NR14xe2x80x94 (where R14 is hydrogen or alkyl), preferably R13 is alkyl, aminoalkyl, carboxyalkyl, phosphonooxyalkyl, sulfooxyalkyl, monosaccharides, hydroxyalkyl, alkoxyalkyl and heterocyclylalkyl (wherein the alkyl chain is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen), more preferably methyl, 2-methoxyethyl, 2-(2-methoxyethoxy)ethyl, 2-(2-hydroxyethoxy)-ethyl, 2-hydroxyethyl, 3,4,5,6-tetrahydroxytetrahydropyran-2-ylmethyl, xe2x80x94(CH2)2OP(O) (OCH3)2, xe2x80x94(CH2) (CHOH) (CH2)OP(O) (OH)2, xe2x80x94(CH2)2OP(O) (OH)2, xe2x80x94(CH2)2OSO3H, xe2x80x94(CH2)2OSO3Na+, xe2x80x94(CH2)3OSO3H, xe2x80x94(CH2)3OSO3Na+, 2,3-dihydroxypropyl, 2-(diethoxyphosphonooxy)-ethyl, 3-(dimethoxy-phosphonooxy)propyl, 3-(diethoxy-phosphonooxy)-propyl, 3-phosphorylnyloxypropyl, 2-hydroxy-3-(dimethoxy-phosphonooxy)-propyl, 2-hydroxy-3-(diethoxy-phosphonooxy)-propyl, 2-diethylaminoethyl, carboxymethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, 2-(2,5-dioxopyrrolidin-1-yl)ethyl, 2-carboxy-2-hydroxyethyl, 3-hydroxypropyl, 2-morpholin-4-ylethyl, pyrrolidin-1-ylethyl, pyrolin-1-yl, 2-hydroxy-3-morpholin-4-ylpropyl, 4-(2-carboxyvinylidene)phenyl, 4-carboxyphenyl, or 2-hydroxy-3-pyrrolidin-1-ylpropyl. Even more preferably R13 is 2-dimethoxyphosphonooxy)ethyl, 2-(diethoxyphosphonooxy)ethyl, 2-phosphonooxyethyl, 3-(dimethoxy-phosphonooxy)propyl, 3-(diethoxyphosphonooxy)propyl, 3-phosphonooxypropyl, xe2x80x94(CH2)3OSO3Na+, 2-hydroxy-3-(dimethoxyphosphonooxy)propyl, 2-hydroxy-3-(diethoxy-phosphonooxy)propyl, 2-hydroxy-3-phosphonooxypropyl, 2,3-dihydroxypropyl, 2-hydroxyethyl or 3-hydroxypropyl, most preferably xe2x80x94(CH2)3OSO3Na+.
Within this group, another more preferred group of compounds is that wherein R6 is xe2x80x94NR15R 6 where R15 and R16 are independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclylalkyl wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, heteroaralkyl, hydroxyalkyl, heterocyclylalkyl or alkoxyalkyl is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in the alkyl chain are optionally replaced by oxygen, xe2x80x94NR17xe2x80x94 (where R17 is hydrogen or alkyl), xe2x80x94Sxe2x80x94, or xe2x80x94SO2xe2x80x94; or R15 and R16 together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino. More preferably, R15 is hydrogen, and R16 is alkyl, aminoalkyl, carboxyalkyl, phosphonooxyalkyl, sulfooxyalkyl, monosaccharides, hydroxyalkyl, alkoxyalkyl, heteroaralkyl, and heterocyclylalkyl (wherein the alkyl chain is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen) or R15 and R16 together with the nitrogen atom to which they are attached form an unsaturated heterocycloamino, more preferably 2-hydroxy-3-morpholin-4-ylpropyl, pyrolin-1-yl, 5-fluoro-2,4-dioxo-pyrimidin-1-yl, 2-hydroxy-3-pyrrolidin-1-ylpropyl, 2-carboxypyrrolidin-1-yl, 2-hydroxy-3-dimethyl-aminopropyl, 2-hydroxy-3-diethylaminopropyl, 2-hydroxy-3-(4-methylpiperazin-1-yl)propyl, 3-[1,2,3]-triazol-1-yl-2-hydroxypropyl, or 2-hydroxy-3-[1,2,3]-triazol-2-ylpropyl.
Another preferred group of compounds within the group represented by Formula (I) is represented by Formula (Ib): 
wherein:
R2 is selected from the group consisting of hydrogen, halo, alkyl, alkylthio, nitro, trihalomethyl, hydroxy, alkoxy, cyano, aryl, heteroaryl, xe2x80x94C(O)R7 (where R7 is selected from the group consisting of alkyl, amino, hydroxy, alkoxy, aryl, heteroaryl, aryloxy, and heteroaryloxy), xe2x80x94NR8R9, xe2x80x94NR8C(O)R9, xe2x80x94SO2R8, and xe2x80x94S(O)2NR8R9 (where R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl);
R3 is selected from the group consisting of hydrogen, alkyl, xe2x80x94C(O)R7 where R7 is selected from the group consisting of alkyl, amino, hydroxy, alkoxy, aryl, heteroaryl, aryloxy, and heteroaryloxy, aryl, and heteroaryl;
R4 is selected from the group consisting of hydrogen, alkyl and xe2x80x94C(O)R7 where R7 is as defined above;
R5 is xe2x80x94COR10 where R10 is alkyl, alkoxy, hydroxy, aryl, aryloxy, heteroaryl, heterocyle, alkylamino, dialkylamino, or xe2x80x94NR11R12 where R11 is hydrogen or alkyl, and R12 is aminoalkyl, dialkylaminoalkyl, heteroarylalkyl, hydroxyalkyl, heteroaralkyl, or heterocyclylalkyl wherein the alkyl chain in alkylamino, heteroaralkyl or heterocylylalkyl is optionally substituted with one or two hydroxy grouP(s);
R6 is:
(i) xe2x80x94OR13 wherein R13 is alkyl, trifluoromethyl, carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, alkoxyalkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, monosaccharides and heterocyclylalkyl wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, heteroaralkyl, hydroxyalkyl or alkoxyalkyl is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen, xe2x80x94NR14xe2x80x94 (where R14 is hydrogen or alkyl), xe2x80x94Sxe2x80x94, or xe2x80x94SO2xe2x80x94; or
(ii) xe2x80x94NR15R16 where are R15 and R16 are independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclylalkyl; wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, heteroaralkyl or alkoxyalkyl is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in the alkyl chain are optionally replaced by oxygen, xe2x80x94NR17xe2x80x94 (where R17 is hydrogen or alkyl), xe2x80x94Sxe2x80x94, or xe2x80x94SO2xe2x80x94; or
R15 and R16 together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino; or
a pharmaceutically acceptable salt thereof.
With this group a more preferred group of compounds is that wherein:
R2 is halo, preferably fluoro, chloro, or bromo, more preferably fluoro;
R3 is selected from the group consisting of hydrogen, alkyl, xe2x80x94C(O)R7, and aryl, preferably methyl, ethyl, propyl, butyl or phenyl, more preferably methyl;
R4 is selected from the group consisting of hydrogen and alkyl, preferably methyl, ethyl, propyl or butyl, more preferably methyl;
R5 is selected from the group consisting of hydrogen and xe2x80x94COR10 where R10 is alkyl, alkoxy, hydroxy, aryl, aryloxy, heteroaryl, heterocyle, alkylamino, dialkylamino, or xe2x80x94NR11R12 where R11 is hydrogen or alkyl, and R12 is alkylaminoalkyl, dialkylaminoalkyl, heteroarylalkyl, hydroxyalkyl, or heterocyclylalkyl, preferably R5 is:
(i) xe2x80x94COR10 where R10 is xe2x80x94NR11R12 where R11 is hydrogen or alkyl and R12 is aminoalkyl, more preferably R5 is 3-amino-2-hydroxypropylaminocarbonyl, N-(2-dimethylaminoethyl)-aminocarbonyl, N-(2-diethylaminoethyl)-N-methylaminocarbonyl, N-(3-dimethylamino-propyl)aminocarbonyl, N-(2-diethylaminoethyl)-aminocarbonyl, N-(3-ethylaminopropyl)aminocarbonyl, N-(3-ethylamino-2-hydroxypropyl)aminocarbonyl, N-(3-diethylamino-propyl)-aminocarbonyl, N-(3-diethylamino-2-hydroxypropyl)-aminocarbonyl, more preferably, N-(2-diethylaminoethyl)-aminocarbonyl; or
(ii) xe2x80x94COR10 where R10 is xe2x80x94NR11R12 where R11 is hydrogen or alkyl and R12 is heterocyclylalkyl wherein the alkyl group is optionally substituted with hydroxy, preferably R5 is 3-pyrrolidin-1-yl-propylaminocarbonyl, 3-morpholin-4-ylpropylamino-carbonyl, 2-pyrrolidin-1-ylethylaminocarbonyl, 2-morpholin-4-ylethylaminocarbonyl, 2-(4-methylpiperazin-1-yl)ethyl-aminocarbonyl, 2-(3,5-dimethylpiperazin-1-yl)ethylamino-carbonyl, 2-(3-ethoxycarbonylpiperazin-1-yl)-ethylamino-carbonyl, 2-(3-oxopiperazin-1-yl)ethylamino-carbonyl, 2-(imidazolidin-1-yl-2-one)ethylaminocarbonyl, 2-(tetrahydropyrimidin-1-yl-2-one)ethylaminocarbonyl, 2-(2-oxopyrrolidin-1-yl)ethylamino-carbonyl, 3-(4-methyl-piperazin-1-yl)propylaminocarbonyl, 3-(3-ethoxycarbonyl-piperazin-1-yl)propylaminocarbonyl, 3-(3-oxopiperazin-1-yl)-propylaminocarbonyl, 3-(imidazolidin-1-yl-2-one)propyl-aminocarbonyl, 3-(tetrahydropyrimidin-1-yl-2-one)propyl-aminocarbonyl, 3-(2-oxopyrrolidin-1-yl)propyl-aminocarbonyl, 2-(2-oxohomopiperidin-1-yl)ethylamino-carbonyl, 3-(2-oxohomo-piperidin-1-yl)propylaminocarbonyl, 3-amino-2-hydroxypropyl-aminocarbonyl, 3-morpholin-2-hydroxypropyl-aminocarbonyl, 3-pyrrolidin-2-hydroxypropylaminocarbonyl, 3-dimethylamino-2-hydroxypropylaminocarbonyl, 3-diethylamino-2-hydroxypropyl-aminocarbonyl, or 3-(4-methylpiperazin-1-yl)-2-hydroxy-propylaminocarbonyl, even more preferably 2-pyrrolidin-1-ylethylaminocarbonyl; or
(iii) xe2x80x94COR10 where R10 is xe2x80x94NR11R12 where R11 is hydrogen or alkyl and R12 is hydroxyalkyl or heteroarylalkyl wherein the alkyl group in heteroaralky is optionally substituted with one or two hydroxy groups, preferably R5 is 3-hydroxypropylamino-carbonyl, 2-hydroxyethylaminocarbonyl, triazin-1-ylpropyl-aminocarbonyl, triazin-1-ylethyl-aminocarbonyl, 3-imidazol-1-ylpropyl-aminocarbony, pyridin-4-ylmethylamino-carbonyl, 3-[1,2,3]-triazol-1-yl-2-hydroxypropyl-aminocarbonyl, 3-[1,2,3]-triazol-2-yl-2-hydroxypropyl-aminocarbonyl, or 2-pyridin-2-ylethylamino-carbonyl; or
(iv) xe2x80x94COR10 where R10 is heterocycle, preferably a heterocycle of 4 or 6 ring atoms containing one or two nitrogen and optionally an oxygen, more preferably R5 is pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl; and
R6 is:
(i) xe2x80x94OR13 wherein R13 is lower alkyl, trifluoromethyl, carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, alkoxyalkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, monosaccharides or heterocyclylalkyl wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, heterocyclylalkyl, hydroxyalkyl, heteroaralkyl, or alkoxyalkyl is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen, or xe2x80x94NR14xe2x80x94 (where R14 is hydrogen or alkyl), preferably R13 is alkyl, aminoalkyl, carboxyalkyl, phosphonooxyalkyl, sulfooxyalkyl, monosaccharides, hydroxyalkyl, alkoxyalkyl and heterocyclylalkyl (wherein the alkyl chain is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen), more preferably methyl, 2-methoxyethyl, 2-(2-methoxyethoxy)ethyl, 2-(2-hydroxyethoxy)-ethyl, 2-hydroxyethyl, 3,4,5,6-tetrahydroxytetrahydropyran-2-ylmethyl, xe2x80x94(CH2)2OP(O) (OCH3)2, xe2x80x94(CH2) (CHOH) (CH2)OP(O) (OH)2, xe2x80x94(CH2)2OP(O) (OH)2, xe2x80x94(CH2)2OSO3H, xe2x80x94(CH2)2OSO3Na+, xe2x80x94(CH2)3OSO3H, xe2x80x94(CH2)3OSO3Na+, 2, 3-dihydroxypropyl, 2-(diethoxyphosphonooxy)-ethyl, 3-(dimethoxy-phosphonooxy)propyl, 3-(diethoxy-phosphonooxy)-propyl, 3-phosphorylnyloxypropyl, 2-hydroxy-3-(dimethoxy-phosphonooxy)-propyl, 2-hydroxy-3-(diethoxy-phosphonooxy)-propyl, 2-diethylaminoethyl, carboxymethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, 2-(2,5-dioxopyrrolidin-1-yl)ethyl, 2-carboxy-2-hydroxyethyl, 3-hydroxypropyl, 2-morpholin-4-ylethyl, pyrrolidin-1-ylethyl, pyrolin-1-yl, 2-hydroxy-3-morpholin-4-ylpropyl, 4-(2-carboxyvinylidene)phenyl, 4-carboxyphenyl, or 2-hydroxy-3-pyrrolidin-1-ylpropyl. Even more preferably R13 is 2-dimethoxyphosphonooxy)ethyl, 2-(diethoxyphosphonooxy)ethyl, 2-phosphonooxyethyl, 3-(dimethoxy-phosphonooxy)propyl, 3-(diethoxyphosphonooxy)propyl, 3-phosphonooxypropyl, 2-hydroxy-3-(dimethoxyphosphonooxy)propyl, 2-hydroxy-3-(diethoxy-phosphonooxy)propyl, 2-hydroxy-3-phosphonooxypropyl, xe2x80x94(CH2)3OSO3Na+, 2,3-dihydroxypropyl, 2-hydroxyethyl or 3-hydroxypropyl, most preferably xe2x80x94(CH2)3OSO3Na+; or
(ii) xe2x80x94NR15R16 where are R15 and R16 R15 and R16 are independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclylalkyl wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, heteroaralkyl, hydroxyalkyl, heterocyclylalkyl or alkoxyalkyl is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in the alkyl chain are optionally replaced by oxygen, xe2x80x94NR 17xe2x80x94 (where R17 is hydrogen or alkyl), xe2x80x94Sxe2x80x94, or xe2x80x94SO2xe2x80x94; or R15 and R16 together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino. More preferably, R15 is hydrogen, and R16 is alkyl, aminoalkyl, carboxyalkyl, phosphonooxyalkyl, sulfooxyalkyl, monosaccharides, hydroxyalkyl, alkoxyalkyl, heteroaralkyl, and heterocyclylalkyl wherein the alkyl chain is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen or R15 and R16 together with the nitrogen atom to which they are attached form an unsaturated heterocycloamino, more preferably 2-hydroxy-3-morpholin-4-ylpropyl, pyrolin-1-yl, 5-fluoro-2,4-dioxo-pyrimidin-1-yl, 2-hydroxy-3-pyrrolidin-1-ylpropyl, 2-carboxypyrrolidin-1-yl, 2-hydroxy-3-dimethylaminopropyl, 2-hydroxy-3-diethylaminopropyl, 2-hydroxy-3-(4-methylpiperazin-1-yl)propyl, 3-[1,2,3]-triazol-1-yl-2-hydroxypropyl, or 2-hydroxy-3-[1,2,3]-triazol-2-ylpropyl.
Listed below are a representative number of compounds of the present invention:
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-morpholin-4-yl-ethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-pyrrolidin-1-yl-ethyl ester;
1-{3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl}-pyrrolidine-2-carboxylic acid;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)-amide;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-(2-oxo-pyrrolidin-1-yl)-ethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid carboxymethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2,3-dihydroxy-propyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-ethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-(2-hydroxy-ethoxy)-ethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-methoxy-ethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid methyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(imidazole-1-carbonyl)-1,3-dihydro-indol-2-one;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-phosphonooxy-propyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-(dimethoxy-phosphonooxy)-propyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-phosphonooxy-propyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-(2,5-dioxopyrrolidin-1-yl)ethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 4-carboxyphenyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 4-(2-carboxyvinylidene)-phenyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-2-carboxyethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2,3,4,5-tetrahydroxypyran-6-ylmethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-phosphonooxyethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-N,N-diethylaminoethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-hydroxypropyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-(dimethoxy-phosphoryloxy)-ethyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-morpholin-4-yl-2-hydroxypropyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-pyrrolidin-1-yl-2-hydroxypropyl ester;
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(5-fluoro-2,4-dioxopyrimidin-1-ylcarbonyl)-1,3-dihydro-indol-2-one; and
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-2-sulfooxypropyl ester sodium salt.
Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mont.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd""s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March""s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about xe2x88x9278xc2x0 C. to about 150xc2x0 C., more preferably from about 0xc2x0 C. to about 125xc2x0 C. and most preferably at about room (or ambient) temperature, e.g., about 20xc2x0 C.
Compounds of Formula (I) can be prepared by following the procedures described below.
Compounds of Formula (I) can be prepared from a compound of Formula (II) as shown in Scheme A below. 
A compound of Formula (I) can be prepared from a 3-(pyrrol-2-ylmethylidene)-2-indolinone of Formula (II) in two steps, as illustrated in Scheme A above.
In step 1,3-(pyrrol-2-ylmethylidene)-2-indolinone (II) is converted to a compound of formula (III) where LG is a suitable leaving group such halo, imidazol-1-yl, and the like by methods well known in the art. For example, a compound of formula (III) where LG is chloro can be prepared by treatment of (II) with a triphosgene in the presence of an organic amine such as triethylamine, pyridine and the like. A compound of formula (III) where LG is imidazol-1-yl can be prepared by treatment of (II) with carbonyl diimidazole under conditions well known in the art.
Compounds of formula (II) can be prepared by following the procedures described below and in U.S. Pat. No. 5,792,783 and Applicants co-pending application Ser. No. 09/783,264, filed on Feb. 15, 2001, and titled xe2x80x9cPYRROLE SUBSTITUTED 2-INDOLINONE PROTEIN KINASE INHIBITORSxe2x80x9d the disclose of which is incorporated herein by reference in its entirety.
In step 2, compound (III) is converted to a compound of Formula (I) where R6 is as defined in the Summary of the Invention by methods well known in the art. For example, a compound of Formula (I) where R6 is xe2x80x94OR13 or xe2x80x94NR15R16 can be prepared by reacting (III) with an alcohol of formula R13OH (where R13 is as defined in the Summary of the invention) under esterfication reaction conditions or an amine of formula xe2x80x94NR15R16 (where R15 and R16 are as defined in the Summary of the Invention) under amination reaction conditions respectively. These reaction conditions are well known in the art. For example, the esterfication of (III) is carried out either in neat alcohol or in a suitable organic solvent such as a chlorinated hydrocarbon e.g., methylene chloride, chloroform and the like, ethereal solution such as tetrahydrofuran, ether, and the like, and dimethylformamide and optionally in the presence of an acid such as hydrochloric acid, acetic acid, trifluoroacetic acid, and the like or a base such as pyridine, triethylamine, and the like. The amination is carried out in any of the above solvent. Here the reaction may optionally be carried out in the presence of other non-nucleophilic base such as pyridine, triethylamine and the like especially if the leaving group is a halo. It will be recognized by a person skilled in the art that other suitable solvents can also be used.
Compounds of formula R13OH and xe2x80x94NR15R16 are commercially available or they can be prepared by methods well known in the art. For example, 2-methoxyethanol, di-(ethylene glycol) methyl ether, 2-(2-hydroxyethoxy)ethyl, diethylene glycol, diethylene glycolamine, di(ethylene glycol)butylether, glycol, glycerol, 2-amino-1-hexanol, 6-aminohexanol, 2-(tert-butylamino)ethanol, N,N-diethanolamine, glycolic acid, 2-(2-oxopyrrolidin-1-yl)ethanol, 2-(2,5-dioxopyrrolidin-1-yl)ethanol, 4-hydroxycinnamic acid, 4-hydroxybenzoic acid, L- and R-glyceric acid, 1,2,3,4-di-O-isopropylidene-D-glactopyranose, 4-(2-hydroxyethyl)morpholine, 2-pyrrolidin-1-ylethanol, proline, 1-amino-4-morpholin-4-propanol, 3-pyrrolidin-1-ylpropane-1,2-diol, 3-pyrrolidino-1,2-propanediol, 3-(dimethylamino)-1,2-propanediol, 3-(n-benzyl-n-methylamino)-1,2-propanediol, 3-(diethylamino)-1,2-propanediol, 3-phenoxy-1,2-propanediol, mephenesin, 3-methoxy-1,2-propanediol, 3-methoxy-1,2-propanediol, glycerol, 3-morpholino-1,2-propanediol, 3-piperidino-1,2-propanediol, 3-amino-1,2-propanediol, 3-(diisopropylamino)-1,2-propanediol, 3-ethoxy-1,2-propanediol, propranolol hydrochloride, propranolol hydrochloride, propranolol hydrochloride, 1-o-benzyl-rac-glycerol, guaifenesin, glyceryl-p-aminobenzoate, glyceryl-p-aminobenzoate, 3-(4-chlorophenoxy)-1,2-propanediol, 3-(2-methoxybenzyloxy)-1,2-propanediol, 3-(2-methylbenzyloxy)-1,2-propanediol, 1,3-diisopropoxy-2-propanol, n-4-(2,3-dihydroxypropyl)sulfanilamide, 3-(2-ethylphenoxy)-1,2-propanediol, 2,3-diacetin, 1-monobutyrin, calcium glycerophosphate, 3-(4-methoxyphenoxy)-1,2-propanediol, 1,3-dihydroxyacetone dimer, 1,3-dihydroxyacetone dimer, oxprenolol hydrochloride, 1-alpha-phosphatidic acid sodium salt, (S)-(xe2x88x92)-1-benzylglycerol, 2,3-dihydroxypropyl acrylate, 3-methylamino-1,2-propanediol, glycerine carbonate, 2,2-bis-(hydroxymethyl)-tetrahydropyran, 6,8-dioxa-1-(hydroxymethyl)bicyclo(3.2.1)octane, 3-mesityloxy-1,2-propanediol, 3-(2-nitroanilino)-1,2-propanediol, 3-benzylamino-propane-1,2-diol, N-ethyl-3-amino-1,2-propanediol, 1-O-propyl-rac-glycerol, monobutyrin, 7,7,9,9-tetramethyl-1,4-dioxa-8-azaspiro[4.5]decane-2-methanol, 1-O-hexyl-rac-glycerol, (S)-(xe2x88x92)-3-tert-butylamino-1,2-propanediol, (2R)-glycerol-O-beta-D-galactopyranoside, galactosyl diglyceride, galactosyl diglyceride, 1-amino-3-phenoxy-2-propanol, 1-phenoxy-3-piperazinopropan-2-ol, (R)-3-t-butylamino-1,2-propanediol, (R)-3-isopropylamino-1,2-propanediol, (S)-3-isopropylamino-1,2-propanediol, 3-(tert-butyl)-5-(hydroxymethyl)-1,3-oxazolan-2-one, (2R)-(xe2x88x92)-1-amino-3-phenoxy-2-propanol, (2S)-(+)-1-amino-3-phenoxy-2-propanol, N-amidino-N-(2,3-dihydroxypropyl)glycine, (S)-3-amino-1,2-propanediol, (R)-3-amino-1,2-propanediol, 4-hydroxytetrahydroisoxazol-2-ium chloride, tolylaldehyde glyceryl acetal, 2-(aminomethyl)-2-furanmethanol, 2,2-dimethyl-1,3-dioxolane-4-methanamine, 15,16-dihydroxy-4,7,10,13-tetraoxa-hexadecylamine hydrochloride, S-N-3-glycerophospho-ethanolamine, (R)-4-aminomethyl-2,2-dimethyl-1,3-dioxolane, (R)-4-aminomethyl-2,2-dimethyl-1,3-dioxolane, choline, 2-anilinoethanol, N-acetylethanolamine, 2-(tert-butylamino)ethanol, N-allyl-Nxe2x80x2-2-hydroxyethylthiourea, N-phenyldiethanolamine, 2-dimethylaminoethanol, N-benzyl-N-methylethanolamine, N-methyldiethanolamine, N-ethyl-N-(2-hydroxyethyl)-m-toluidine, 2-diethylaminoethanol, N-ethyldiethanolamine, N,N-bis(2-hydroxyethyl)-m-chloroaniline, 2-ethoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monomethyl ether, 1-(2-hydroxyethyl)pyrrolidine, N-(2-hydroxyethyl)iminodiacetic acid, 1-aziridineethanol, N-(2-hydroxyethyl)phthalimide, N-(2-hydroxyethyl)piperazine, 1-amino-4-(2-hydroxyethyl)piperazine, 1,4-bis(2-hydroxyethyl)piperazine, HEPES, HEPPS, N-(2hydroxyethyl)morpholine, 1-piperidineethanol, 2-nitroethanol, 2-hydroxyethylhydrazine, ethanolamine, 2-(diisopropylamino)-ethanol, 2-[[2-(dimethylamino)ethyl]methylamino]ethanol, 2-(dibutylamino)ethanol, N-nitrosodiethanolamine, 2-(N-methylanilino)ethanol, 2-(N-methylanilino)ethanol, 2-(N-ethylanilino)ethanol, N-tert-butyldiethanolamine, isopropyldiethanolamine, diethyl bis(2-hydroxyethyl)amino methyl phosphonate, 2-(hexamethyleneimino)ethanol, N-cyclohexylethanolamine, 1-(2-hydroxyethyl)imidazolidine-2-thione, 2-(N-benzyl-N-(2-hydroxyethyl)aminomethyl)-3-hydroxypyridine, 2-(4-sulfanilylanilino)ethanol, 1-(2-hydroxyethyl)-3-(2-methoxy-5-methylphenyl)urea, 2-hydroxyethyl carbazate, 1-(2-hydroxyethyl)-3,4,5,6-tetrahydropyrimidine-2(1h)-thione, DMAE bitartrate, N,N-diethylethanolammonium chloride, N,N-diethylethanolammonium chloride, HEPES sodium salt, N-(2-hydroxyethyl)lactamide, 1-(2-hydroxyethyl)-2-imidazolidinone, N-(2-hydroxyethyl)-2-phenylacetamide, N-(2-hydroxyethyl)-4-cyclohexene-1,2-dicarboximide, N-(2-hydroxyethyl)oxazolidine, 2-(N-methyl-N-isopropylamino)ethanol, 2-(N-methylethylamino)ethanol, N-(xcex2-hydroxyethyl)pyrazole, 2-hydroxyethyl 3-mercaptopropionate, 3-(2-hydroxyethyl)-quinazoline-2,4-dione, ethylene glycol mono-tert-butyl ether, 2-hydroxyethylurea, N-(2-hydroxyethyl)propionamide, 2-isobutoxyethanol, 2-[2-(dimethylamino)ethoxy]ethanol, N-(hydroxyethyl)-acetoacetamide, HEPPS sodium salt, 3-(2-hydroxyethylamino)-5,5-dimethyl-2-cyclohexen-1-one, N-(2-hydroxyethyl)succinimide, ethyl N-(2-hydroxyethyl)-carbamate, 2-(dimethylaminomethyl)-3-hydroxy-1-(2-hydroxyethyl)piperidine, 2,6-dimethyl-4-morpholineethanol, 1-(2-hydroxyethyl)-3-(2,4-xylyl)-2-thiourea, 1-ethyl-1-(2-hydroxyethyl)-3-phenylurea, 5-chloro-N-(2-hydroxyethyl)phthalimide, 1-(4-chloro-2-(trifluoromethyl)phenyl)-3-(2-hydroxyethyl)urea, N-methyl-1-phenyl-2,2xe2x80x2-iminodiethanol, 4-(2-hydroxyethyl)-1-lambda-6,4-thiazinane-1,1-dione, N-cyclohexyl-Nxe2x80x2-(2-hydroxyethyl)thiourea, N-cyclopropyl-Nxe2x80x2-(2-hydroxyethyl)thiourea, N-benzyl-Nxe2x80x2-(2-hydroxyethyl)thiourea, MENAI E627, N-(2xe2x80x2-hydroxyethyl)-3,5-dihydroxybenzamide, N-hydroxyethyl-3-nitrobenzenesulfonamide, 4-nitrotoluenehydroxyethylsulfamide, HEPES sodium salt hydrate, 4-(2-hydroxyethyl)piperazine-1-(2-hydroxypropanesulfonic acid) monohydrate, 2-(1,2,3,4-tetrahydro-2,2,4,7-tetramethyl-1-quinolyl)-1-ethanol, etanidazole, 2-(5-nitro-1-imidazolyl)-1-ethanol, 4-(2-hydroxyethyl)-piperazine-1-carboxylic acid-ethylester, 1-(4-fluorobenzyl)-4-(2-hydroxyethyl)piperazine, 2-[4-(6-chloro-1,3-benzothiazol-2-yl)piperazino]ethan-1-ol, 1-(2-hydroxyethyl)-2-methylimidazole, 2(2-isobutoxyethoxy)ethanol, N-cycloheptyl-Nxe2x80x2-(2-hydroxyethyl)thiourea, N-(2-hydroxyethyl)-maleimide, 2-[4-(2-fluorobenzyl)piperazino]ethan-1-ol, 1-(2-hydroxyethyl)piperidine-4-carboxamide, maltitol, D-(+)-turanose, alpha-D-glucoheptose, 3-O-methylglucose, methyl-alpha-D-glucopyranoside, alpha-D-glucose-6-phosphate, monosodium salt, alpha-D-glucose 1-phosphate dipotassium salt dihydrate, and alpha-D-melibiose H2O.
The compounds of Formula (I) are prodrugs of compounds of Formula (II) that inhibit PKs such as receptor tyrosine kinases (RTKs) and cellular tyrosine kinases (CTKs), and serine-threonine kinases (STKs). The compounds of the present invention are thereofore useful in the treatment of diseases mediated by abnormal PK activity. The PKs whose catalytic activity is modulated by the compounds of this invention include protein tyrosine kinases of which there are two types, receptor tyrosine kinases (RTKs) and cellular tyrosine kinases (CTKs), and serine-threonine kinases (STKs). RTK mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic effects on the extracellular microenvironment, etc.). See, Schlessinger and Ullrich, 1992, Neuron 9:303-391.
It has been shown that tyrosine phosphorylation sites on growth factor receptors function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Fantl et al., 1992, Cell 69:413-423, Songyang et al., 1994, Mol. Cell. Biol. 14:2777-2785), Songyang et al., 1993, Cell 72:767-778, and Koch et al., 1991, Science 252:668-678. Several intracellular substrate proteins that associate with RTKs have been identified. They may be divided into two principal groups: (1) substrates that have a catalytic domain, and (2) substrates which lack such domain but which serve as adapters and associate with catalytically active molecules. Songyang et al., 1993, Cell 72:767-778. The specificity of the interactions between receptors and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. Songyang et al., 1993, Cell 72:767-778. These observations suggest that the function of each RTK is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
STKs, being primarily cytosolic, affect the internal biochemistry of the cell, often as a down-line response to a PTK event. STKs have been implicated in the signaling process which initiates DNA synthesis and subsequent mitosis leading to cell proliferation.
Thus, PK signal transduction results in, among other responses, cell proliferation, differentiation, growth and metabolism. Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, glioblastoma and hemangioma, disorders such as leukemia, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy and other disorders related to uncontrolled angiogenesis and/or vasculogenesis.
A precise understanding of the mechanism by which the compounds of this invention inhibit PKs is not required in order to practice the present invention. However, while not hereby being bound to any particular mechanism or theory, it is believed that the compounds interact with the amino acids in the catalytic region of PKs. PKs typically possess a bi-lobate structure wherein ATP appears to bind in the cleft between the two lobes in a region where the amino acids are conserved among PKs. Inhibitors of PKs are believed to bind by non-covalent interactions such as hydrogen bonding, van der Waals forces and ionic interactions in the same general region where the aforesaid ATP binds to the PKs. More specifically, it is thought that the 2-indolinone component of the compounds of this invention binds in the general space normally occupied by the adenine ring of ATP. Specificity of a particular molecule for a particular PK may then arise as the result of additional interactions between the various substituents on the 2-indolinone core and the amino acid domains specific to particular PKs. Thus, different indolinone substituents may contribute to preferential-binding to particular PKs. The ability to select compounds active at different ATP (or other nucleotide) binding sites makes the compounds of this invention useful for targeting any protein with such a site. The compounds disclosed herein thus have utility in in vitro assays for such proteins as well as exhibiting in vivo therapeutic effects through interaction with such proteins.
Additionally, the compounds of the present invention provide a therapeutic approach to the treatment of many kinds of solid tumors, including but not limited to carcinomas, sarcomas including Kaposi""s sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma. Treatment or prevention of non-solid tumor cancers such as leukemia are also contemplated by this invention. Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers and bone cancers.
Further examples, without limitation, of the types of is disorders related to inappropriate PK activity that the compounds described herein may be useful in preventing, treating and studying, are cell proliferative disorders, fibrotic disorders and metabolic disorders.
Cell proliferative disorders, which may be prevented, treated or further studied by the present invention include cancer, blood vessel proliferative disorders and mesangial cell proliferative disorders.
Blood vessel proliferative disorders refer to disorders related to abnormal vasculogenesis (blood vessel formation) and angiogenesis (spreading of blood vessels). While vasculogenesis and angiogenesis play important roles in a variety of normal physiological processes such as embryonic development, corpus luteum formation, wound healing and organ regeneration, they also play a pivotal role in cancer development where they result in the formation of new capillaries needed to keep a tumor alive. Other examples of blood vessel proliferation disorders include arthritis, where new capillary blood vessels invade the joint and destroy cartilage, and ocular diseases, like diabetic retinopathy, where new capillaries in the retina invade the vitreous, bleed and cause blindness.
Two structurally related RTKs have been identified to bind VEGF with high affinity: the fms-like tyrosine 1 (fit-1) receptor (Shibuya et al., 1990, Oncogene,5:519-524; De Vries et al., 1992, Science, 255:989-991) and the KDR/FLK-1 receptor, also known as VEGF-R2. Vascular endothelial growth factor (VEGF) has been reported to be an endothelial cell specific mitogen with in vitro endothelial cell growth promoting activity. Ferrara and Henzel, 1989, Biochein. Biophys. Res. Comm., 161:851-858; Vaisman et al., 1990, J. Biol. Chem., 265:19461-19566. Information set forth in U.S. application Ser. Nos. 08/193,829, 08/038,596 and 07/975,750, strongly suggest that VEGF is not only responsible for endothelial cell proliferation, but also is the prime regulator of normal and pathological angiogenesis. See generally, Klagsburn and Soker, 1993, Current Biology, 3(10)699-702; Houck, et al., 1992, J. Biol. Chem., 267:26031-26037.
Normal vasculogenesis and angiogenesis play important roles in a variety of physiological processes such as embryonic development, wound healing, organ regeneration and female reproductive processes such as follicle development in the corpus luteum during ovulation and placental growth after pregnancy. Folkman and Shing, 1992, J. Biological Chem., 267(16):10931-34. Uncontrolled vasculogenesis and/or angiogenesis has been associated with diseases such as diabetes as well as with malignant solid tumors that rely on vascularization for growth. Klagsburn and Soker, 1993, Current Biology, 3(10):699-702; Folkham, 1991, J. Natl. Cancer Inst., 82:4-6; Weidner, et al., 1991, New Engl. J. Med., 324:1-5.
The surmised role of VEGF in endothelial cell proliferation and migration during angiogenesis and vasculogenesis indicates an important role for the KDR/FLK-1 receptor in these processes. Diseases such as diabetes mellitus (Folkman, 198, in XIth Congress of Thrombosis and Haemostasis (Verstraeta, et al., eds.), pp. 583-596, Leuven University Press, Leuven) and arthritis, as well as malignant tumor growth may result from uncontrolled angiogenesis. See e.g., Folkman, 1971, N. Engl. J. Med., 285:1182-1186. The receptors to which VEGF specifically binds are an important and powerful therapeutic target for the regulation and modulation of vasculogenesis and/or angiogenesis and a variety of severe diseases which involve abnormal cellular growth caused by such processes. Plowman, et al., 1994, DNandP, 7(6):334-339. More particularly, the KDR/FLK-1 receptor""s highly specific role in neovascularization make it a choice target for therapeutic approaches to the treatment of cancer and other diseases which involve the uncontrolled formation of blood vessels.
Thus, the present invention provides compounds capable of regulating and/or modulating tyrosine kinase signal transduction including KDR/FLK-1 receptor signal transduction in order to inhibit or promote angiogenesis and/or vasculogenesis, that is, compounds that inhibit, prevent, or interfere with the signal transduced by KDR/FLK-1 when activated by ligands such as VEGF. Although it is believed that the compounds of the present invention act on a receptor or other component along the tyrosine kinase signal transduction pathway, they may also act directly on the tumor cells that result from uncontrolled angiogenesis.
Although the nomenclature of the human and murine counterparts of the generic xe2x80x9cflk-Ixe2x80x9d receptor differ, they are, in many respects, interchangeable. The murine receptor, Flk-1, and its human counterpart, KDR, share a sequence homology of 93.4% within the intracellular domain. Likewise, murine FLK-I binds human VEGF with the same affinity as mouse VEGF, and accordingly, is activated by the ligand derived from either species. Millauer et al., 1993, Cell, 72:835-846; Quinn et al., 1993, Proc. Natl. Acad. Sci. USA, 90:7533-7537. FLK-1 also associates with and subsequently tyrosine phosphorylates human RTK substrates (e.g., PLC-xcex3 or p85) when co-expressed in 293 cells (human embryonal kidney fibroblasts).
Models which rely upon the FLK-1 receptor therefore are directly applicable to understanding the KDR receptor. For example, use of the murine FLK-1 receptor in methods which identify compounds that regulate the murine signal transduction pathway are directly applicable to the identification of compounds which may be used to regulate the human signal transduction pathway, that is, which regulate activity related to the KDR receptor. Thus, chemical compounds identified as inhibitors of KDR/FLK-1 in vitro, can be confirmed in suitable in vivo models. Both in vivo mouse and rat animal models have been demonstrated to be of excellent value for the examination of the clinical potential of agents acting on the KDR/FLK-1 induced signal transduction pathway.
Thus, the present invention provides compounds that regulate, modulate and/or inhibit vasculogenesis and/or angiogenesis by affecting the enzymatic activity of the KDR/FLK-1 receptor and interfering with the signal transduced by KDR/FLK-1. Thus the present invention provides a therapeutic approach to the treatment of many kinds of solid tumors including, but not limited to, glioblastoma, melanoma and Kaposi""s sarcoma, and ovarian, lung, mammary, prostate, pancreatic, colon and epidermoid carcinoma. In addition, data suggests the administration of compounds which inhibit the KDR/Flk-1 mediated signal transduction pathway may also be used in the treatment of hemangioma, restenois and diabetic retinopathy.
Furthermore, this invention relates to the inhibition of vasculogenesis and angiogenesis by other receptor-mediated pathways, including the pathway comprising the flt-1 receptor.
Receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and autophosphorylation. Binding sites are thereby created for intracellular signal transduction molecules which leads to the formation of complexes with a spectrum of cytoplasmic signalling molecules that facilitate the appropriate cellular response, e.g., cell division and metabolic effects to the extracellular microenvironment. See, Schlessinger and Ullrich, 1992, Neuron, 9:1-20.
The close homology of the intracellular regions of KDR/FLK-1 with that of the PDGF-xcex2 receptor (50.3% homology) and/or the related flt-1 receptor indicates the induction of overlapping signal transduction pathways. For example, for the PDGF-xcex2 receptor, members of the src family (Twamley et al., 1993, Proc. Natl. Acad. Sci. USA, 90:7696-7700), phosphatidylinositol-3xe2x80x2-kinase (Hu et al., 1992, Mol. Cell. Biol., 12:981-990), phospholipase cxcex3 (Kashishian and Cooper, 1993, Mol. Cell. Biol., 4:49-51), ras-GTPase-activating protein, (Kashishian et al., 1992, EMBO J., 11:1373-1382), PTP-ID/syp (Kazlauskas et al., 1993, Proc. Natl. Acad. Sci. USA, 10 90:6939-6943), Grb2 (Arvidsson et al., 1994, Mol. Cell. Biol., 14:6715-6726), and the adapter molecules Shc and Nck (Nishimura et al., 1993, Mol. Cell. Biol., 13:6889-6896), have been shown to bind to regions involving different autophosphorylation sites. See generally, Claesson-Welsh, 1994, Prog. Growth Factor Res., 5:37-54. Thus, it is likely that signal transduction pathways activated by KDR/FLK-1 include the ras pathway (Rozakis et al., 1992, Nature, 360:689-692), the PI-3xe2x80x2-kinase, the src-mediated and the plcxcex3-mediated pathways. Each of these pathways may play a critical role in the angiogenic and/or vasculogenic effect of KDR/FLK-1 in endothelial cells. Consequently, a still further aspect of this invention relates to the use of the organic compounds described herein to modulate angiogenesis and vasculogenesis as such processes are controlled by these pathways.
Conversely, disorders related to the shrinkage, contraction or closing of blood vessels, such as restenosis, are also implicated and may be treated or prevented by the methods of this invention.
Fibrotic disorders refer to the abnormal formation of extracellular matrices. Examples of fibrotic disorders include hepatic cirrhosis and mesangial cell proliferative disorders. Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar. An increased extracellular matrix resulting in a hepatic scar can also be caused by a viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis. Other fibrotic disorders implicated include atherosclerosis.
Mesangial cell proliferative disorders refer to disorders brought about by abnormal proliferation of mesangial cells. Mesangial proliferative disorders include various human renal diseases such as glomerulonephritis, diabetic nephropathy and malignant nephrosclerosis as well as such disorders as thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies. The RTK PDGFR has been implicated in the maintenance of mesangial cell proliferation. Floege et al., 1993, Kidney International 43:47S-54S.
Many cancers are cell proliferative disorders and, as noted previously, PKs have been associated with cell proliferative disorders. Thus, it is not surprising that PKs such as, for example, members of the RTK family have been associated with the development of cancer. Some of these receptors, like EGFR (Tuzi et al., 1991, Br. J. Cancer 63:227-233, Torp et al., 1992, APMIS 100:713-719) HER2/neu (Slamon et al., 1989, Science 244:707-712) and PDGF-R (Kumabe et al., 1992, Oncogene, 7:627-633) are over-expressed in many tumors and/or persistently activated by autocrine loops. In fact, in the most common and severe cancers these receptor over-expressions (Akbasak and Suner-Akbasak et al., 1992, J. Neurol. Sci., 111:119-133, Dickson et al., 1992, Cancer Treatment Res. 61:249-273, Korc et al., 1992, J. Clin. Invest. 90:1352-1360) and autocrine loops (Lee and Donoghue, 1992, J. Cell. Biol., 118:1057-1070, Korc et al., supra, Akbasak and Suner-Akbasak et al., supra) have been demonstrated. For example, EGFR has been associated with squamous cell carcinoma, astrocytoma, glioblastoma, head and neck cancer, lung cancer and bladder cancer. HER2 has been associated with breast, ovarian, gastric, lung, pancreas and bladder cancer. PDGFR has been associated with glioblastoma and melanoma as well as lung, ovarian and prostate cancer. The RTK c-met has also been associated with malignant tumor formation. For example, c-met has been associated with, among other cancers, colorectal, thyroid, pancreatic, gastric and hepatocellular carcinomas and lymphomas. Additionally c-met has been linked to leukemia. Over-expression of the c-met gene has also been detected in patients with Hodgkins disease and Burkitts disease.
IGF-IR, in addition to being implicated in nutritional support and in type-II diabetes, has also been associated with several types of cancers. For example, IGF-I has been implicated as an autocrine growth stimulator for several tumor types, e.g. human breast cancer carcinoma cells (Arteaga et al., 1989, J. Clin. Invest. 84:1418-1423) and small lung tumor cells (Macauley et al., 1990, Cancer Res., 50:2511-2517). In addition, IGF-I, while integrally involved in the normal growth and differentiation of the nervous system, also appears to be an autocrine stimulator of human gliomas. Sandberg-Nordqvist et al., 1993, Cancer Res. 53:2475-2478. The importance of IGF-IR and its ligands in cell proliferation is further supported by the fact that many cell types in culture (fibroblasts, epithelial cells, smooth muscle cells, T-lymphocytes, myeloid cells, chondrocytes and osteoblasts (the stem cells of the bone marrow)) are stimulated to grow by IGF-I. Goldring and Goldring, 1991, Eukaryotic Gene Expression,1:301-326. Baserga and Coppola suggest that IGF-IR plays a central role in the mechanism of transformation and, as such, could be a preferred target for therapeutic interventions for a broad spectrum of human malignancies. Baserga, 1995, Cancer Res., 55:249-252, Baserga, 1994, Cell 79:927-930, Coppola et al., 1994, Mol. Cell. Biol., 14:4588-4595.
STKs have been implicated in many types of cancer including, notably, breast cancer (Cance, et al., Int. J. Cancer, 54:571-77 (1993)).
The association between abnormal PK activity and disease is not restricted to cancer. For example, RTKs have been associated with diseases such as psoriasis, diabetes mellitus, endometriosis, angiogenesis, atheromatous plaque development, Alzheimer""s disease, restenosis, von Hippel-Lindau disease, epidermal hyperproliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas. For example, EGFR has been indicated in corneal and dermal wound healing. Defects in Insulin-R and IGF-1R are indicated in type-II diabetes mellitus. A more complete correlation between specific RTKs and their therapeutic indications is set forth in Plowman et al., 1994, DNandP 7:334-339.
As noted previously, not only RTKs but CTKs including, but not limited to, src, abl, fps, yes, fyn, lyn, lck, blk, hck, fgr and yrk (reviewed by Bolen et al., 1992, FASEB J., 6:3403-3409) are involved in the proliferative and metabolic signal transduction pathway and thus could be expected, and have been shown, to be involved in many PTK-mediated disorders to which the present invention is directed. For example, mutated src (v-src) has been shown to be an oncoprotein (pp60v-src) in chicken. Moreover, its cellular homolog, the proto-oncogene pp60c-src transmits oncogenic signals of many receptors. Over-expression of EGFR or HER2/neu in tumors leads to the constitutive activation of pp60c-src, which is characteristic of malignant cells but absent in normal cells. On the other hand, mice deficient in the expression of c-src exhibit an osteopetrotic phenotype, indicating a key participation of c-src in osteoclast function and a possible involvement in related disorders.
Similarly, Zap70 has been implicated in T-cell signaling which may relate to autoimmune disorders.
STKs have been associated with inflammation, autoimmune disease, immunoresponses, and hyperproliferation disorders such as restenosis, fibrosis, psoriasis, osteoarthritis and rheumatoid arthritis.
PKs have also been implicated in embryo implantation. Thus, the compounds of this invention may provide an effective method of preventing such embryo implantation and thereby be useful as birth control agents. Additional disorders which may be treated or prevented using the compounds of this invention are immunological disorders such as autoimmune disease, AIDS and cardiovasular disorders such as atherosclerosis.
Finally, both RTKs and CTKs are currently suspected as being involved in hyperimmune disorders.
A compound of the present invention or a pharmaceutically acceptable salt thereof, can be administered as such to a human patient or can be administered in pharmaceutical compositions in which the foregoing materials are mixed with suitable carriers or excipient(s). Techniques for formulation and administration of drugs may be found in xe2x80x9cRemington""s Pharmacological Sciences,xe2x80x9d Mack Publishing Co., Easton, Pa., latest edition.
As used herein, xe2x80x9cadministerxe2x80x9d or xe2x80x9cadministrationxe2x80x9d refers to the delivery of a compound of Formula (I) or a pharmaceutically acceptable salt thereof or of a pharmaceutical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof of this invention to an organism for the purpose of prevention or treatment of a PK-related disorder.
Suitable routes of administration may include, without limitation, oral, rectal, transmucosal or intestinal administration or intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreal, intraperitoneal, intranasal, or intraocular injections. The preferred routes of administration are oral and intravenous.
Alternatively, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a solid tumor, often in a depot or sustained release formulation.
Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with tumor-specific antibody. The liposomes will be targeted to and taken up selectively by the tumor.
Pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
For injection, the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks"" solution, Ringer""s solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient. Pharmaceutical preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding other suitable auxiliaries if desired, to obtain tablets or dragee cores. Useful excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as, for example, maize starch, wheat starch, rice starch and potato starch and other materials such as gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinyl-pyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid. A salt such as sodium alginate may also be used.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers may be added in these formulations, also.
Pharmaceutical compositions which may also be used include hard gelatin capsules. As a non-limiting example, the active compound capsule oral drug product formulation may be as 50 and 200 mg dose strengths (formulation codes J-011248-AA-00 and J-011248-AA-01, respectively). The two dose strengths are made from the same granules by filling into different size hard gelatin capsules, size 3 for the 50 mg capsule and size 0 for the 200 mg capsule. The composition of the formulation may be, for example, as indicated in Table 1.
The capsules may be packaged into brown glass or plastic bottles to protect the active compound from light. The containers containing the active compound capsule formulation must be stored at controlled room temperature (15-30xc2x0 C.).
For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds may also be formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical compositions for parenteral administration include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound.
Additionally, suspensions of the active compounds may be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
In addition to the fomulations described previously, the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. A compound of this invention may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a pharamcologically acceptable oil), with ion exchange resins, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt.
A non-limiting example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer and an aqueous phase such as the VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:D5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of such a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80, the fraction size of polyethylene glycol may be varied, other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone, and other sugars or polysaccharides may substitute for dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. In addition, certain organic solvents such as dimethylsulfoxide also may be employed, although often at the cost of greater toxicity.
Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
The pharmaceutical compositions herein also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Many of the PK modulating compounds of the invention may be provided as physiologically acceptable salts wherein the claimed compound may form the negatively or the positively charged species. Examples of salts in which the compound forms the positively charged moiety include, without limitation, quaternary ammonium (defined elsewhere herein), salts such as the hydrochloride, sulfate, carbonate, lactate, tartrate, malate, maleate, succinate wherein the nitrogen atom of the quaternary ammonium group is a nitrogen of the selected compound of this invention which has reacted with the appropriate acid. Salts in which a compound of this invention forms the negatively charged species include, without limitation, the sodium, potassium, calcium and magnesium salts formed by the reaction of a carboxylic acid group in the compound with an appropriate base (e.g. sodium hydroxide (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca(OH)2), etc.).
Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose, e.g., the modulation of PK activity or the treatment or prevention of a PK-related disorder.
More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
For any compound used in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from cell culture assays. Then, the dosage can be formulated for use in animal models so as to achieve a circulating concentration range that includes the IC50 as determined in cell culture (i.e., the concentration of the test compound which achieves a half-maximal inhibition of the PK activity). Such information can then be used to more accurately determine useful doses in humans.
Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the IC50 and the LD50 (both of which are discussed elsewhere herein) for a subject compound. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient""s condition. (See e.g., Fingl, et al., 1975, in xe2x80x9cThe Pharmacological Basis of Therapeuticsxe2x80x9d, Ch. 1 p.1).
Dosage amount and interval may be adjusted individually to provide plasma levels of the active species which are sufficient to maintain the kinase modulating effects. These plasma levels are referred to as minimal effective concentrations (MECs). The MEC will vary for each compound but can be estimated from in vitro data, e.g., the concentration necessary to achieve 50-90% inhibition of a kinase may be ascertained using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations.
Dosage intervals can also be determined using MEC value. Compounds should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. At present, the therapeutically effective amounts of compounds of Formula (I) may range from approximately 25 mg/m2 to 1500 mg/m2 per day; preferably about 3 mg/m2/day. Even more preferably 50 mg/qm qd to 400 mg/qd.
In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration and other procedures known in the art may be employed to determine the correct dosage amount and interval.
The amount of a composition administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
The compositions may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or of human or veterinary administration. Such notice, for example, may be of the labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Suitable conditions indicated on the label may include treatment of a tumor, inhibition of angiogenesis, treatment of fibrosis, diabetes, and the like.
It is also an aspect of this invention that a compound described herein might be combined with other chemotherapeutic agents for the treatment of the diseases and disorders discussed above. For instance, a compound, salt or prodrug of this invention might be combined with alkylating agents such as fluorouracil (5-FU) alone or in further combination with leukovorin; or other alkylating agents such as, without limitation, other pyrimidine analogs such as UFT, capecitabine, gemcitabine and cytarabine, the alkyl sulfonates, e.g., busulfan (used in the treatment of chronic granulocytic leukemia), improsulfan and piposulfan; aziridines, e.g., benzodepa, carboquone, meturedepa and uredepa; ethyleneimines and methylmelamines, e.g., altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; and the nitrogen mustards, e.g., chlorambucil (used in the treatment of chronic lymphocytic leukemia, primary macroglobulinemia and non-Hodgkin""s lymphoma), cyclophosphamide (used in the treatment of Hodgkin""s disease, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilm""s tumor and rhabdomyosarcoma), estramustine, ifosfamide, novembrichin, prednimustine and uracil mustard (used in the treatment of primary thrombocytosis, non-Hodgkin""s lymphoma, Hodgkin""s disease and ovarian cancer); and triazines, e.g., dacarbazine (used in the treatment of soft tissue sarcoma).
A compound of this invention can also be used in combination with other antimetabolite chemotherapeutic agents such as, without limitation, folic acid analogs, e.g. methotrexate (used in the treatment of acute lymphocytic leukemia, choriocarcinoma, mycosis fungiodes breast cancer, head and neck cancer and osteogenic sarcoma) and pteropterin; and the purine analogs such as mercaptopurine and thioguanine which find use in the treatment of acute granulocytic, acute lymphocytic and chronic granulocytic leukemias.
It is contemplated that a compound of this invention can also be used in combination with natural product based chemotherapeutic agents such as, without limitation, the vinca alkaloids, e.g., vinblastin (used in the treatment of breast and testicular cancer), vincristine and vindesine; the epipodophylotoxins, e.g., etoposide and teniposide, both of which are useful in the treatment of testicular cancer and Kaposi""s sarcoma; the antibiotic chemotherapeutic agents, e.g., daunorubicin, doxorubicin, epirubicin, mitomycin (used to treat stomach, cervix, colon, breast, bladder and pancreatic cancer), dactinomycin, temozolomide, plicamycin, bleomycin (used in the treatment of skin, esophagus and genitourinary tract cancer); and the enzymatic chemotherapeutic agents such as L-asparaginase.
In addition to the above, a compound of this invention could also be used in combination with the platinum coordination complexes (cisplatin, etc.); substituted ureas such as hydroxyurea; methylhydrazine derivatives, e.g., procarbazine; adrenocortical suppressants, e.g., mitotane, aminoglutethimide; and hormone and hormone antagonists such as the adrenocorticosteriods (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate); estrogens (e.g., diethylstilbesterol); antiestrogens such as tamoxifen; androgens, e.g., testosterone propionate; and aromatase inhibitors such as anastrozole.
Finally, it is also contemplated that the combination of a compound of this invention will be effective in combination with mitoxantrone or paclitaxel for the treatment of solid tumor cancers or leukemias such as, without limitation, acute myelogenous (non-lymphocytic) leukemia. The compounds of this invention can also be used with a COX-2 inhibitor.